1. Field of the Invention
The present invention relates to fused ring 4-oxopyrimidine derivatives.
2. Related Background Art
In living creatures including mammals, histamine, an endogenous factor with physiological activity, functions as a neurotransmitter and has far-reaching pharmacological effects (e.g., Life science, Vol. 17, p. 503 (1975)).
From immunohistochemical research, it has become clear that histaminergic (production) soma are present in the tubercle mammillary nuclei of the posterior hypothalmic region, and histaminergic nerve fibers extend over a very large area within the brain, which suggests that histamine has many different pharmacological actions (e.g., Journal of Comprehensive Neurology, Vol. 273, p. 283).
The presence of a histaminergic nerve in the tubercle mammillary nuclei of the posterior hypothalamic region suggests that histamine plays a particularly important role in cerebral function in controlling the physiology of the hypothalmus, i.e., in waking rhythms, internal secretions, food/water intake and sexual behavior (e.g., Progress in Neurobiology, Vol. 63, p. 637 (2001)).
The fact that there are projections of histaminergic nerve fibers to regions of the brain related to maintenance of the waking state (e.g., the cerebral cortex) suggests that histamine has a role in maintaining the waking state or the waking-sleep cycle. Also, the fact that there are projections of histaminergic nerve fibers to many peripheral structures such as the hippocampus or tonsil-like complex suggest that it has a role in regulating the autonomic nervous system and emotions, control of motivation, learning and memory.
After histamine is released from cells producing histamine, it interacts with specific polymers called receptors on the cell membrane surface or in target cells, which account for its pharmacological effects and regulation of body functions. Four types of histamine receptors have so far been discovered. Histamine H3 receptors have been shown by various pharmacological and physiological studies to participate in the function of central and peripheral nerves (e.g., Trends in Pharmacological Science, Vol. 8, p. 24 (1986)), and in recent years, man and rodent histamine H3 receptor genes have been identified (e.g., Molecular Pharmacology, Vol. 55, p. 1101 (1999)).
It has been shown that histamine H3 receptors are present in the center or the presynaptic membrane of peripheral nerve cells, functioning as autoreceptors, controlling the release of histamine and also controlling the release of other neurotransmitters. Specifically, it has been reported that histamine H3 receptor agonists, antagonists or inverse-agonists regulate the release of histamine, noradrenalin, serotonine, acetylcholine or dopamine from synaptic endings. For example, release of neurotransmitters such as (R)-(α)-methylhistamine is suppressed by agonists, and is promoted by antagonists or inverse-agonists like thioperamide (e.g., Trends in Pharmacological Science, Vol. 19, p. 177 (1998)).